Chandrakanthan Vashe, Yeola Avani, Kwan Jair C, Oliver Rema A, Qiao Qiao, Kang Young Chan, Zarzour Peter, Beck Dominik, Boelen Lies, Unnikrishnan Ashwin, Villanueva Jeanette E, Nunez Andrea C, Knezevic Kathy, Palu Cintia, Nasrallah Rabab, Carnell Michael, Macmillan Alex, Whan Renee, Yu Yan, Hardy Philip, Grey Shane T, Gladbach Amadeus, Delerue Fabien, Ittner Lars, Mobbs Ralph, Walkley Carl R, Purton Louise E, Ward Robyn L, Wong Jason W H, Hesson Luke B, Walsh William, Pimanda John E
Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia; Surgical and Orthopaedic Research Laboratories, UNSW Australia, Sydney, NSW 2052, Australia;
Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):E2306-15. doi: 10.1073/pnas.1518244113. Epub 2016 Apr 4.
Current approaches in tissue engineering are geared toward generating tissue-specific stem cells. Given the complexity and heterogeneity of tissues, this approach has its limitations. An alternate approach is to induce terminally differentiated cells to dedifferentiate into multipotent proliferative cells with the capacity to regenerate all components of a damaged tissue, a phenomenon used by salamanders to regenerate limbs. 5-Azacytidine (AZA) is a nucleoside analog that is used to treat preleukemic and leukemic blood disorders. AZA is also known to induce cell plasticity. We hypothesized that AZA-induced cell plasticity occurs via a transient multipotent cell state and that concomitant exposure to a receptive growth factor might result in the expansion of a plastic and proliferative population of cells. To this end, we treated lineage-committed cells with AZA and screened a number of different growth factors with known activity in mesenchyme-derived tissues. Here, we report that transient treatment with AZA in combination with platelet-derived growth factor-AB converts primary somatic cells into tissue-regenerative multipotent stem (iMS) cells. iMS cells possess a distinct transcriptome, are immunosuppressive, and demonstrate long-term self-renewal, serial clonogenicity, and multigerm layer differentiation potential. Importantly, unlike mesenchymal stem cells, iMS cells contribute directly to in vivo tissue regeneration in a context-dependent manner and, unlike embryonic or pluripotent stem cells, do not form teratomas. Taken together, this vector-free method of generating iMS cells from primary terminally differentiated cells has significant scope for application in tissue regeneration.
组织工程学的当前方法旨在生成组织特异性干细胞。鉴于组织的复杂性和异质性，这种方法存在局限性。另一种方法是诱导终末分化细胞去分化为具有再生受损组织所有成分能力的多能增殖细胞，蝾螈利用这种现象来再生肢体。5-氮杂胞苷（AZA）是一种核苷类似物，用于治疗白血病前期和白血病血液疾病。AZA也已知可诱导细胞可塑性。我们假设AZA诱导的细胞可塑性通过短暂的多能细胞状态发生，并且同时暴露于一种感受性生长因子可能导致可塑性和增殖性细胞群体的扩增。为此，我们用AZA处理定向分化的细胞，并筛选了一些在间充质来源组织中具有已知活性的不同生长因子。在此，我们报告AZA与血小板衍生生长因子-AB联合短暂处理可将原代体细胞转化为组织再生多能干细胞（iMS细胞）。iMS细胞具有独特的转录组，具有免疫抑制作用，并表现出长期自我更新、连续克隆形成能力和多胚层分化潜能。重要的是，与间充质干细胞不同，iMS细胞以依赖于环境的方式直接促进体内组织再生，并且与胚胎干细胞或多能干细胞不同，不会形成畸胎瘤。综上所述，这种从原代终末分化细胞生成iMS细胞的无载体方法在组织再生中具有重要的应用前景。
